Sensorimotor control of breathing in the mdx mouse model of Duchenne muscular dystrophy.

KEY POINTS: Respiratory failure is a leading cause of mortality in Duchenne muscular dystrophy (DMD), but little is known about the control of breathing in DMD and animal models. We show that young (8 weeks of age) mdx mice hypoventilate during basal breathing due to reduced tidal volume. Basal CO2 production is equivalent in wild-type and mdx mice. We show that carotid bodies from mdx mice have blunted responses to hyperoxia, revealing hypoactivity in normoxia. However, carotid body, ventilatory and metabolic responses to hypoxia are equivalent in wild-type and mdx mice. Our study revealed profound muscle weakness and muscle fibre remodelling in young mdx diaphragm, suggesting severe mechanical disadvantage in mdx mice at an early age. Our novel finding of potentiated neural motor drive to breathe in mdx mice during maximal chemoactivation suggests compensatory neuroplasticity enhancing respiratory motor output to the diaphragm and probably other accessory muscles. ABSTRACT: Patients with Duchenne muscular dystrophy (DMD) hypoventilate with consequential arterial blood gas derangement relevant to disease progression. Whereas deficits in DMD diaphragm are recognized, there is a paucity of knowledge in respect of the neural control of breathing in dystrophinopathies. We sought to perform an analysis of respiratory control in a model of DMD, the mdx mouse. In 8-week-old male wild-type and mdx mice, ventilation and metabolism, carotid body afferent activity, diaphragm muscle force-generating capacity, and muscle fibre size, distribution and centronucleation were determined. Diaphragm EMG activity and responsiveness to chemostimulation was determined. During normoxia, mdx mice hypoventilated, owing to a reduction in tidal volume. Basal CO2 production was not different between wild-type and mdx mice. Carotid sinus nerve responses to hyperoxia were blunted in mdx, suggesting hypoactivity. However, carotid body, ventilatory and metabolic responses to hypoxia were equivalent in wild-type and mdx mice. Diaphragm force was severely depressed in mdx mice, with evidence of fibre remodelling and damage. Diaphragm EMG responses to chemoactivation were enhanced in mdx mice. We conclude that there is evidence of chronic hypoventilation in young mdx mice. Diaphragm dysfunction confers mechanical deficiency in mdx resulting in impaired capacity to generate normal tidal volume at rest and decreased absolute ventilation during chemoactivation. Enhanced mdx diaphragm EMG responsiveness suggests compensatory neuroplasticity facilitating respiratory motor output, which may extend to accessory muscles of breathing. Our results may have relevance to emerging treatments for human DMD aiming to preserve ventilatory capacity.

Tuberculosis Aortitis and Mycotic Pseudo-aneurysm of the Infra-renal Aorta after Intravesicular BCG Therapy.

We report a patient who presented with a rapidly expanding symptomatic tuberculous aortitis and mycotic pseudo-aneurysm of the infra-renal aorta, after intra-vesical BCG chemotherapy for bladder cancer, treated by required emergency open aneurysm repair. His case highlights this rare complication of intravesical BCG treatment, haematological seeding causing tuberculous aortitis and mycotic pseudo-aneurysm formation of the infra-renal aorta. It also illustrates successful treatment with emergency open surgery, local debridement of mycotic pseudoaneurysm, in-situ surgical reconstruction using a custom bovine-wrap interposition graft to create a neo-aorta and multi-agent anti-tuberculous chemotherapy.

Midterm Analysis of Survival and Cause of Death Following Endovascular Abdominal Aortic Aneurysm Repair.

PURPOSE: To assess rates of complications, secondary interventions, survival, and cause of death following endovascular abdominal aortic aneurysm (AAA) repair over a 10-year period. MATERIALS AND METHODS: Single-institution retrospective cohort study of all patients undergoing primary endovascular aortic aneurysm repair (EVAR) between July 2006 and June 2015. The population constituted 175 patients with 163 fusiform and 12 saccular AAAs. Of these, 149 (85%) were male, with mean age 75.4 (±7.1) years. Patients were followed up until June 30, 2016. Cause of death was determined from the national death register. RESULTS: Mean follow-up was 34.4 (±24.4) months. The secondary intervention rate was 9.7%, and there were 4 aneurysm ruptures (0.8% annual incidence). Thirty-day mortality was 0.6%. Survival at 1, 3, and 5 years was 93.1%, 84%, and 64.9%, respectively. Forty-eight patients died during follow-up, 3 secondary to rupture, leading to overall and aneurysm-related death rates of 9.7 and 0.6 per 100 person-years. All other deaths were due to nonaneurysm causes, most commonly cardiovascular (n = 15), pulmonary (n = 13), and malignancy (n = 9). Baseline renal impairment ( P < .001), ischemic heart disease ( P < .05), age greater than 75 years ( P < .05), and urgent/emergency EVAR were associated with inferior long-term survival. Type II endoleak negatively influenced fusiform aneurysm sac regression ( P = .02), but there was no association between survival and occurrence of any complication or secondary intervention. CONCLUSION: The majority of deaths during medium-term follow-up post-EVAR are due to nonaneurysm-related causes. Survival is determined by the following baseline factors: renal impairment, ischemic heart disease, advanced age, and the presence of a symptomatic/ruptured aneurysm.

What's in a Name? Exploring the Nomenclature of Science Communication in the UK.

This study, via a consideration of the literature, and a survey of science communicators, presents concise and workable definitions for science outreach, public engagement, widening participation, and knowledge exchange, in a UK context.   Sixty-six per cent of participants agreed that their definitions of outreach, public engagement, and widening participation aligned with those of their colleagues, whilst 64% felt that their personal definitions matched those of their institute. However, closer inspection of the open-ended questions found the respondents often differed in the use of the nomenclature. In particular, the respondents found it difficult to define knowledge exchange in this context.

A cautionary tale on the use of antiplatelet treatment following TURP.

A pleasant 74-year-old man was discharged home following a complication-free transurethral resection of his prostate (TURP) and successful trial without catheter. Unfortunately, on postoperative day 6, he presented to A&E with chest pain requiring emergency intervention for a confirmed myocardial infarction. A drug-eluting stent was inserted into his right coronary artery and he was started on dual antiplatelet therapy of aspirin and clopidogrel. On day 7, the patient developed significant haematuria requiring transfusion and an obstructive uropathy, requiring an emergency laparotomy and 1 L of organised clot evacuation from his bladder. The dual antiplatelet treatment was restarted on day 4 postlaparotomy, following debate between both the cardiology and urology teams regarding its appropriate reintroduction. On day 7, he was rushed back to the theatre for a re-laparotomy after CT confirmed reaccumulation of clot following an acute deterioration at ward level. The patient made an excellent recovery and was discharged home with regular outpatient follow-up.

Belly button piercings: a saving grace? A patent urachus presenting in a 17-year-old girl.

We report the case of a 17-year-old girl who presented to the accident and emergency department with dysuria and foul smelling, bloody discharge from her umbilicus. The definitive diagnosis was that of a patent urachus, which is a fistulous communication between the bladder and the umbilicus, usually diagnosed in early infancy. The incidence of a patent urachus is approximately 1 in 70,000 in the general population. It is highly likely that removal of a recent belly button piercing resulted in the acute presentation by completing the fistulous tract to the skin. This case is of clinical relevance as the diagnosis was missed 18 months prior with a milder presentation. The recommended treatment option is surgical excision due to the potential risk of malignant change, with urachal adenocarcinoma accounting for 0.3% of all bladder cancers.

Antisense oligonucleotides in the treatment of bladder cancer.

This review examines the role that antisense oligonucleotides play in the treatment of superficial and muscle-invasive bladder cancer. The unique environment of the urinary bladder allows intravesical instillation of antisense oligonucleotides, and researchers have already demonstrated uptake of antisense oligonucleotides in models of bladder cancer. Second, proof of principle has been established by demonstrating downregulation of the antisense target mRNA and protein. Third, and most importantly from a therapeutic perspective, synergy between chemotherapy and antisense oligonucleotides has been shown in bladder cancer models in vitro and in vivo. The collective evidence points to a role for antisense oligonucleotides in the treatment of superficial and muscle-invasive bladder cancer in combination with existing treatment modalities.

The role of antisense oligonucleotides in the treatment of bladder cancer.

Both intravesical and systemic chemotherapy are limited in their efficacy in the treatment of bladder cancer patients. These limitations are centred around an inability to induce apoptosis in bladder tumour cells. This resistance to apoptosis induction is commonly associated with the overexpression of antiapoptotic proteins such as Bcl-2. Strategies to decrease the cellular expression of such proteins would enhance chemotherapy effectiveness. One such strategy is to use antisense oligonucleotides which are short sequence specific single stranded DNA or RNA molecules designed to bind to the RNA of the target protein. By binding to the target RNA, protein production is interrupted and target protein levels decease. When used to target antiapoptotic proteins, antisense oligonucleotides can therefore be used as a pre-treatment before chemotherapy to help chemosensitise the tumour cell. This review outlines the rationale for this strategy and the work done to date with antisense oligonucleotides in bladder cancer.

Oligoclonality in bladder cancer: the implication for molecular therapies.

PURPOSE: There is conflicting evidence in the published literature regarding the clonal or oligoclonal origin of bladder cancer. MATERIALS AND METHODS: A MEDLINE search of articles on the clonality, genetic, epigenetic and tumor microenvironment of bladder cancer cells was done. Laboratory and clinical studies were included and relevant articles were selected if tumor cell clonality was part of the study. We reviewed this published evidence. RESULTS: Current thinking proposes 2 main theories. 1) In the clonogenic theory multifocal and recurrent tumors evolve from a single transformed cell and, hence, all progeny share a number of identical genetic mutations. 2) The field change theory assumes a global change in the urothelium with multiple transformed cells evolving into mature tumors independently. The evidence for and against each theory is compelling. Of equal importance are the parallel epigenetic modifications and changes in the cellular microenvironment that permit tumor evolution. CONCLUSIONS: The presence of oligoclonality has implications for the potential efficacy of novel molecular therapeutic agents for bladder cancer. The molecular targets for such therapies must be widely sampled in a tumor population to assess expression in separate clones.